Genetically modified vesicular stomatitis virus (VSV) is an attractive agent for cancer treatment due to rapid intratumoral replication and observed clinical responses. Although VSV selectively kills malignant cells and can boost antitumor immunity, limited induction of intratumoral immune infiltration remains a barrier to efficacy in some cancer models. Here we engineered the oncolytic VSV platform to encode the T cell chemokine CXCL9, which is known to mediate the recruitment of activated CD8⁺ cytotoxic T cells and CD4⁺ T helper cells, and demonstrates conserved protein function between mice and humans. Chemotactic activity of the virally encoded chemokine was confirmed in vitro. Intratumoral concentration of CXCL9 was shown to increase after VSV therapy in three different cancer models, but to a much greater degree after VSV-CXCL9 therapy as compared with VSV control viruses. Despite a steep chemokine gradient from the tumor to the bloodstream, tumor trafficking of adoptively transferred and endogenous T cells was not measurably increased following VSV-CXCL9 therapy. Our results indicate that oncolytic VSV infection promotes release of CXCL9 in the tumor microenvironment, but further boosting of the functional chemokine gradient through virus engineering has little incremental impact on intratumoral immune cell infiltration in mouse and human tumor models.

由于快速的肿瘤内复制和观察到的临床反应，转基因的水疱性口炎病毒（VSV）是一种有吸引力的癌症治疗剂。尽管VSV选择性杀死恶性细胞并可以增强抗肿瘤免疫力，但在某些癌症模型中，肿瘤内免疫浸润的有限诱导仍然是疗效的障碍。在这里，我们设计了溶瘤性VSV平台来编码T细胞趋化因子CXCL9，已知它介导活化的CD8 ⁺细胞毒性T细胞和CD4 ⁺ T辅助细胞的募集，并证明了人与人之间保守的蛋白质功能。在体外证实了病毒编码的趋化因子的趋化活性。在三种不同的癌症模型中，在VSV治疗后，CXCL9的肿瘤内浓度显示增加，但在VSV-CXCL9治疗后，与VSV对照病毒相比，CXCL9的肿瘤内浓度增加了很多。尽管从肿瘤到血流的趋化因子梯度陡峭，但是在VSV-CXCL9治疗后，过继转移和内源性T细胞的肿瘤运输并未明显增加。我们的结果表明溶瘤性VSV感染促进肿瘤微环境中CXCL9的释放，但是通过病毒工程进一步提高功能趋化因子梯度对小鼠和人类肿瘤模型中的肿瘤内免疫细胞浸润几乎没有增量影响。